Project 02: Tumor Methylomics Analysis Link with Racial Disparities in Ovarian Cancer

项目02：肿瘤甲基组学分析与卵巢癌种族差异的联系

• 批准号: 10488640
• 负责人: Daniela E Matei
• 金额: $ 25.8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488640
• 关键词: Aberrant DNA Methylation; Accounting; Address; Affect; African American; Apoptotic; Area; Attitude; Belief; Biologic Characteristic; Biological; Biological Assay; Biological Factors; Biology; Cancer Center; Carboplatin; Caring; Centers for Disease Control and Prevention (U.S.); Chicago; Clinical; Clinical Trials; Communities; CpG Islands; DNA Methylation; DNA Modification Process; DNA Sequence Alteration; DNA methylation profiling; Data; Development; Diagnosis; Disease; Disease Progression; Environmental Risk Factor; Epigenetic Process; Event; Future; Gene Expression; Gene Silencing; Genes; Goals; Grant; Health Services Accessibility; Histologic; Hospitals; In Vitro; Intervention; Knowledge; Link; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measurable; Measures; Medical; Methylation; Mission; Modeling; Modernization; Molecular; National Cancer Institute; National Cancer Program; Neoplasm Metastasis; Oncogenic; Organoids; Outcome; Pathway interactions; Patients; Persons; Platinum; Play; Pre-Clinical Model; Public Health; Recurrence; Relapse; Reporting; Research; Resistance; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; SEER Program; Scientific Advances and Accomplishments; Serous; Socioeconomic Factors; Socioeconomic Status; Survival Rate; Therapeutic Intervention; Therapeutic Studies; Treatment outcome; Tumor Suppression; Tumor Suppressor Proteins; United States; Universities; Validation; Woman; Work; anticancer research; base; bead chip; bench to bedside; bioinformatics tool; black women; cancer health disparity; cancer initiation; care delivery; chemotherapy; differences in access; epigenetic marker; epigenomics; geographic disparity; health equity; histone modification; in vivo; insight; methylation pattern; methylome; methylomics; metropolitan; neoplasm registry; novel therapeutics; ovarian neoplasm; patient derived xenograft model; patient population; pre-clinical; pyrosequencing; racial difference; racial disparity; response; screening; socioeconomics; therapeutic evaluation; tissue resource; transcriptome sequencing; transcriptomics; treatment response; tumor

Abstract: Ovarian cancer (OC) remains the deadliest gynecologic cancer and recent cancer registry-based analyses reported significantly reduced survival rates among African American (AA) women compared to white (W) women with ovarian cancer, despite similar stage distribution and histological types at diagnosis. This disparity could be accounted for by differences in access to medical care and other socioeconomic factors, but also by differences in biological characteristics which may impact response to treatment. Little is known about differences in racially-defined biological key determinants of OC disparity and adequate models to study these differences are not yet available. Here we propose to begin addressing this unmet need by focusing on epigenetic factors, particularly on DNA methylation, which we hypothesize functions as a link between socio- economic or environmental factors and genomic alterations to modify disease course and response to therapy. Racial differences in DNA methylation events in ovarian cancer have not been yet defined. An additional unmet need is the development of adequate preclinical models (organoids, patient-derived xenografts) that could be used to measure response to treatment and that will reflect the unique biology of OC in AA vs. white women. To address these questions, we propose two aims, which will be integrated into the larger scope of this pre- SPORE application addressing disparities in gynecologic cancer and which will leverage our expertise on DNA methylation and preclinical therapeutic testing in OC. In specific aim 1, we propose to define the methylome of high-grade serous OC in AA and white patients by using tissue resources from the Lurie Cancer Center and affiliated Stroger Hospital, which serve the greater Chicago metropolitan area, including a high proportion of AA women. To accomplish this goal, we will use the Infinium HumanMethylation950 BeadChip array and we will validate key differences in CpG island methylation by pyrosequencing. For specific aim 2, we will begin developing high-grade serous ovarian cancer-derived patient derived xenografts (PDX) and organoids from AA and white women and we will assess response of these models to platinum in vitro and in vivo. RNA-sequencing and DNA methylation arrays will provide integrative gene expression and methylome signatures associated with response to treatment for models derived from AA and white women. At the completion of this project, we would have identified key oncogenic drivers regulated epigenetically in tumors from AA vs. white women and we would have generated useful new resources to continue to address biological questions related to racial differences in OC response to treatment.

摘要： 卵巢癌(OC)仍然是最致命的妇科癌症，最近基于癌症登记的分析 据报道，非裔美国人(AA)女性的存活率明显低于白人(W) 卵巢癌患者，尽管诊断时的分期分布和组织学类型相似。这种差异 这可能是由于获得医疗保健的机会和其他社会经济因素的差异，但也是 可能影响治疗反应的生物学特性的差异。人们对此知之甚少 种族定义的OC差异的生物学关键决定因素的差异以及研究这些差异的适当模型 目前还没有差异可用。在这里，我们建议通过专注于以下几个方面来解决这一未得到满足的需求 表观遗传因素，特别是DNA甲基化，我们假设它的功能是连接社会和 经济或环境因素和基因组改变，以改变病程和对治疗的反应。 卵巢癌DNA甲基化事件的种族差异尚未确定。另一个未满足的问题 需要的是开发足够的临床前模型(有机化合物，患者来源的异种移植)，这可能是 用来衡量对治疗的反应，这将反映再生障碍性贫血与白人女性中OC的独特生物学特征。至 针对这些问题，我们提出了两个目标，这两个目标将被整合到这个更大的范围内 孢子应用解决妇科癌症的差异，并将利用我们在 卵巢癌的DNA甲基化和临床前治疗试验。在具体目标1中，我们建议定义 利用来自Lurie的组织资源分析再生障碍性贫血和白人患者的高级别血清OC的甲基组 癌症中心和附属斯特罗格医院，服务于大芝加哥大都市区，包括一个 AA级女性比例较高。为了实现这一目标，我们将使用Infinium HumanMethylation950珠片 我们将通过焦磷酸测序来验证CpG岛甲基化的关键差异。对于特定的目标2，我们 将开始开发高级别浆液性卵巢癌患者来源的异种移植物(PDX)和 我们将评估这些模型在体外和体内对铂的反应。 活着。RNA测序和DNA甲基化阵列将提供整合的基因表达和甲基组 与AA和白人女性模特的治疗反应相关的签名。在 这个项目的完成，我们将确定在肿瘤中受表观遗传调控的关键致癌驱动因素 我们将产生有用的新资源来继续解决 与OC对治疗反应的种族差异有关的生物学问题。